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(Circulation Research. 2004;94:1375.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Bradykinin B₁ Receptor Expression Induced by Tissue Damage in the Rat Portal Vein

A Critical Role for Mitogen-Activated Protein Kinase and Nuclear Factor-B Signaling Pathways

Rodrigo Medeiros, Daniela A. Cabrini, Juliano Ferreira, Elizabeth S. Fernandes, Marcelo A.S. Mori, João B. Pesquero, Michael Bader, Maria C.W. Avellar, Maria M. Campos, João B. Calixto

From the Department of Pharmacology (R.M., D.A.C., J.F., E.S.F, M.M.C., J.B.C), Universidade Federal de Santa Catarina, Brazil; Department of Pharmacology (M.C.W.A) and Department of Biophysics (M.A.S.M., J.B.P.), Universidade Federal de São Paulo, Brazil; Max Delbrück Centre for Molecular Medicine (D.A.C., M.B.), Berlin-Buch, Germany.

Correspondence to João B. Calixto, Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Rua Ferreira Lima, 82, 88015-420, Florianópolis, SC, Brazil. E-mail calixto{at}farmaco.ufsc.br or calixto3{at}terra.com.br

The bradykinin B₁ receptor (B₁R) is normally absent under physiological conditions, but is highly inducible during inflammatory conditions or following tissue damage. The present study attempted to determine some of the mechanisms underlying B₁R upregulation following tissue injury in rat portal vein. Damage induced by tissue isolation and in vitro incubation caused a significant and time-dependent increase in des-Arg⁹–bradykinin (des-Arg⁹–BK) responsiveness that paralleled the B₁R mRNA expression, as confirmed by real-time quantitative PCR. In vitro incubation of rat portal vein also induced the activation of some members of the mitogen activated protein kinase (MAPK) family, namely, extracellular signal-regulated kinase (ERK), c-Jun NH₂-terminal kinase (JNK), and p38 MAPK, an effect accompanied by degradation of the inhibitory protein IB and translocation of nuclear transcription factor-B (NF-B) to the nucleus. The blockade of p38 MAPK, JNK or NF-B, but not ERK pathways with selective inhibitors, resulted in a significant reduction of the upregulated contractile response caused by the selective B₁R agonist des-Arg⁹–BK, and largely prevented the induction of B₁R mRNA expression in the rat portal vein. Together, these results demonstrate that in vitro tissue damage induces activation of several intracellular signaling pathways that have a key role in the control of B₁R expression. B₁R could exert a pivotal role in the development of the cardiovascular response associated with vascular damage.

Key Words: receptor, bradykinin B₁tissue damage • mitogen-activated protein kinases • portal vein • rats

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